Specificity of Ubiquitination

描述(申请人提供)：泛素和泛素样蛋白(Ublps)的翻译后修饰是一种主要的细胞调控机制。泛素化调控着大量的生物过程，包括细胞分裂、免疫反应和胚胎发育。因此，泛素途径的缺陷与许多疾病有关，特别是癌症，以及与衰老相关的疾病，如神经退行性疾病和干性肌肉萎缩。除了泛素，在高等真核生物中还发现了10多个ublp。Ublp的结构和序列与泛素非常相似，但它们将目标指向不同的命运。因此，了解定义泛素化过程的特异性的分子基础是很重要的。我们的长期目标是了解泛素和ublp是如何针对它们的特定靶点来控制涉及癌症和神经退行性疾病等疾病的过程。泛素通过一系列三种酶的级联作用与靶点连接，这三种酶分别是E1、E2和E3。尽管这些酶很重要，但人们对泛素化酶是如何选择泛素的知之甚少。我们假设泛素化酶的特异性是由与泛素相互作用的正选择和对错误的ublp的负选择的组合决定的。我们的重点是参与细胞增殖和调控肿瘤抑制蛋白的E1、E2和E3酶。由于这些酶对细胞增殖很重要，并在导致癌症的途径中发挥作用，因此这些酶可能是抗有丝分裂药物的良好靶点。蛋白酶体抑制剂Bortezomib(VelcadeTM)最近被批准用于治疗多发性骨髓瘤，突显了针对泛素和ublp途径中的酶的治疗潜力，并强调了了解这些酶的详细机制和特异性的重要性。我们计划采用一种多学科的方法，将泛素化酶、ublp连接级联中的酶、突变体和复合体的生化、酶学和结构分析结合起来，以了解泛素化的特异性。

DESCRIPTION (provided by applicant): Post-translational modification by ubiquitin and ubiquitin-like proteins (ublps) is a predominant cellular regulatory mechanism. Ubiquitination regulates a vast array of biological processes, including cell division, the immune response, and embryonic development. As a result, defects in the ubiquitin pathway are associated with numerous diseases, particularly cancer, and disorders associated with aging, such as neurodegenerative disorders and arid muscle wasting. In addition to ubiquitin, over 10 ublps have been found in higher eukaryotes. Ublps have structures and sequences that closely resemble ubiquitin, but they direct their targets to distinct destinies. Therefore, it is important to understand the molecular bases that define the specificity of the ubiquitination process. Our long-term goal is to understand how ubiquitin and ublps are directed to their particular targets to control processes involved in diseases such as cancers and neurodegenerative disorders. Ubiquitin is ligated to targets by a cascade involving a series of three enzymes in classes known as E1, E2, and E3. Despite the importance of these enzymes, little is known how ubiquitin is selected by ubiquitinating enzymes. We hypothesize that the specificity of ubiquitinating enzymes is dictated by a combination of positive selection for interacting with ubiquitin, and negative selection against the wrong ublp. We are focusing on the E1, E2 and E3 enzymes involved in cell proliferation and involved in regulating tumor suppressor proteins. Because these enzymes are important for cell proliferation, and play roles in pathways that lead to cancers, these enzymes may serve as good targets for anti-mitogenic agents. The recent approval of the proteasome inhibitor Bortezomib (VelcadeTM) for treatment of multiple myeloma underscores the therapeutic potential for targeting enzymes in the ubiquitin, and ublp, pathways, and highlights the importance of understanding the detailed mechanisms and specificities of these enzymes. We plan a multidisciplinary approach that combines biochemical, enzymological and structural analysis of ubiquitinating enzymes, enzymes in ublp conjugation cascades, mutants and complexes, in order to understand the specificity of ubiquitination.